The challenges of identifying clinically useful anti-cancer drugs and obtaining FDA approval for marketing can often be exacerbated by incidences of resistance of the drug in cancer patients. For example, ibrutinib is an orally bioavailable and highly specific inhibitor of Bruton tyrosine kinase (BTK) that was recently approved for treatment of patients with recurrent chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Ibrutinib has also shown efficacy in subsets of patients with diffuse large B cell lymphoma (DLBCL) and Waldenstrom macroglobulinaemia (WM). However, despite activity in multiple B-cell malignancies, cases of primary and secondary resistance have emerged along with predictions that the incidence of observed resistance will increase as clinical use expands over time. Zhang et al., Br. J. Haematol. 170(4):445-56 (2015). Although the suspected mechanism of resistance has been elucidated (a C481→S mutation in the BTK gene), further studies have shown that at least two other cellular mechanisms appear to override the inhibitory action of ibrutinib in resistant cancer cells, leading to proposals of using ibrutinib in combination with palbociclib or palbociclib followed by idelalisib. See, Sinha, “Overcoming Mantle Cell Lymphoma's Ibrutinib Resistance,” in JNCI, 106(11), 2014.
In view of the foregoing, a need remains for anti-cancer drugs that are efficacious and which could treat cancer patients, such as patients whose cancer has proven resistant or refractory to FDA-approved front-line therapy.